Acetylcholinesterase inhibitors containing 1-benzyl-pyridinium salts

ABSTRACT

The present invention provides an excellent acetylcholinesterase inhibitor. That is, it provides an acetylcholinesterase inhibitor comprising a 1-benzylpyridinium salt represented by the following formula:  
                 
 
     wherein R 1 , R 2 , R 3  and R 4  are the same as or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, a C 1-6  alkyl group, a C 1-6  alkoxy group etc.; R 5  represents a hydrogen atom, a halogen atom etc.; the partial structure:  
                 
 
     is a group represented by the formula &gt;C(R 6 )—CH 2 — (wherein R 6  is a hydrogen atom or a halogen atom) or &gt;C═CH—; X−represents a halide ion or organic sulfonic acid ion; and m is 0 or an integer from 1 to 5.

TECHNICAL FIELD

[0001] The present invention relates to a novel acetylcholinesteraseinhibitor.

PRIOR ART

[0002] Usefulness of an acetylcholinesterase inhibitor as an agent fortreating and improving senile dementia such as Alzheimer type seniledementia, or cerebrovascular dementia, attention deficit hyperactivitydisorder etc. came to be clinically highly regarded. In particular,donepezil hydrochloride(1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidinehydrochloride) found with efforts of the present inventors is the onlyacetylcholinesterase inhibitor at present which can be sufficientlyuseful in respect of pharmacological activity, side effects,administration frequency, administration form etc., and fulfilling hopesof many patients and their families in nursing and clinical fields. Inaddition to donepezil hydrochloride, there are knownacetylcholinesterase inhibitors such as rivastigmine(3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate),metrifonate (dimethyl 2,2,2-trichloro-1-hydroxyethyl)phosphate), tacrinehydrochloride (1,2,3,4-tetrahydro-9-acridinamine), galanthaminehydrobromide, neostigmine, physostigmine etc. On one hand, there aresome reports on processes for producing donepezil derivatives includingdonepezil hydrochloride, and for example JP-A 8-225527 and JP-A11-263774 disclose a process for producing benzylpiperidylmethylindanones, characterized by hydrogenating pyridinium salts with hydrogenin the presence of a hydrogenating catalyst.

[0003] It has been desired to provide highly useful acetylcholinesteraseinhibitors in addition to donepezil hydrochloride.

DISCLOSURE OF THE INVENTION

[0004] In view of the circumstances described above, the presentinventors made extensive study through which they found that both acompound represented by the formula:

[0005] (wherein the “a” moieties are the same as or different from eachother and each represents a hydrogen atom or a C₁₋₆ alkoxy group; n isan integer from 1 to 4; and X⁽⁻⁾ represents a halide ion) and a compoundrepresented by the formula:

[0006] (wherein b, c, d and e are the same as or different from eachother and each represents a hydrogen or a linear or branched C₁₋₆ alkyl,C₁₋₆alkoxy, C₁₋₆alkoxy carbonyl, C₁₋₆alkyl aminocarbonyloxy, di(C₁₋₆alkyl)-aminocarbonyloxy or a halogen; and X″⁽⁻⁾ represents an anionin the series of chloride, bromide, iodide and sulfate) exhibit anexcellent inhibitory action on acetylcholinesterase. Further, on thebasis of these findings, they found that a 1-benzylpyridinium saltrepresented by the formula:

[0007] (wherein R¹, R², R³ and R⁴ are the same or different, andrepresent a hydrogen atom, a halogen atom, a hydroxyl group, a nitrilegroup, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆alkoxy carbonylgroup, a C₁₋₆ alkyl aminocarbonyloxy group or a di (C₁₋₆alkyl)-aminocarbonyloxy group; R⁵ represents a hydrogen atom, a halogenatom, a C₁₋₆alkyl group, a C₂₋₆ alkenyl group or a C₂₋₆ alkynyl group;the partial structure:

[0008] is a group represented by the formula >C(R⁶)—CH₂— (wherein R⁶ isa hydrogen atom or a halogen atom) or >C═CH—; X⁻ represents a halide ionor organic sulfonic acid ion; and m is 0 or an integer from 1 to 5)exhibits an excellent inhibitory action on acetylcholinesterase, andaccomplished the present invention.

[0009] That is, the first aspect according to the present invention is(1) an acetylcholinesterase inhibitor comprising a 1-benzylpyridiniumsalt represented by the above formula (I). Further, (2) in the aboveitem (1), R¹, R², R³ and R⁴ may be the same as or different from eachother and each represents a hydrogen atom or a C₁₋₆ alkoxy group; (3) inthe above item (1), R¹, R² R³ and R⁴ may be the same as or differentfrom each other and each represents a hydrogen atom or a methoxy group;(4) in the above item (1) , R¹ and R⁴ may represent a hydrogen atom; andR² and R³ may represent a methoxy group; (5) in the above item (1), R⁵may be a hydrogen atom; (6) in the above item (1), the partialstructure:

[0010] may be a group represented by the formula >C (R⁶) —CH₂— (whereinR⁶ is a hydrogen atom or a halogen atom) ; (7) in the above item (1), mmay be 0, 2 or 4; (8) in the above item (1), the halide ion representedby X⁻ maybe a chloride ion, bromide ion or iodide ion, preferably achloride ion or bromide ion; (9) in the above item (1), the organicsulfonic acid ion represented by X⁻ may be a methanesulfonate ion,trifluoromethanesulfonate ion, ethanesulfonate ion, benzenesulfonateion, toluenesulfonate ion or camphor sulfonate ion; (10) in the aboveitem (1), the 1-benzylpyridinium salt may be a compound represented bythe formula:

[0011] wherein R¹, R², R³, R⁴ and X⁻ have the same meanings as definedabove; and n is an integer from 1 to 6; (11) in the above item (1), the1-benzylpyridinium salt may be a compound represented by the formula:

[0012] wherein R¹, R², R³, R⁴ and X⁻ have the same meanings as definedabove; and p is 0 or an integer from 1 to 5; (12) in the above item (1),the preparation may be an agent for treating, preventing or improvingsenile dementia, cerebrovascular dementia or attention deficithyperactivity disorder; and (13) in the above item (12), the seniledementia may be Alzheimer type senile dementia.

[0013] The second aspect according to the present invention is (14) apharmaceutical preparation comprising a 1-benzylpyridinium saltrepresented by the formula:

[0014] wherein R¹, R², R³, R⁴, R⁵, the partial structure:

[0015] X⁻ and m have the same meanings as defined above. Further, thethird aspect according to the present invention is (15) use of a1-benzylpyridinium salt represented by the formula:

[0016] (wherein R¹, R², R³, R⁴, R⁵, the partial structure:

[0017] X⁻ and m have the same meanings as defined above) for producingan acetylcholinesterase inhibitor.

[0018] The present invention provides a method of preventing, treatingor improving a disease against which an inhibitory action onacetylcholinesterase is efficacious for prevention, treatment orimprovement, by administering a pharmacologically effective dose of the1-benzylpyridinium salt represented by the above formula (I) to apatient.

[0019] In the present invention, the disease against which an inhibitoryaction on acetylcholinesterase is efficacious for prevention, treatmentor improvement includes senile dementia such as Alzheimer type seniledementia, and cerebrovascular dementia and attention deficithyperactivity disorder.

[0020] Hereinafter,, the meanings of symbols, terms etc. used in thespecification are described, and the present invention is described indetail.

[0021] In the specification, the structural formulae of the compoundmay, for convenience' sake, indicate a certain isomer, but the presentinvention encompasses all possible isomers which can occur in thestructures of the compound, for example geometric isomer, optical isomerbased on asymmetrical carbon, stereoisomer and tautomer, and a mixtureof such isomers, so the compound according to the present invention maybe any isomers or a mixture thereof without limitation to the formulaeshown for convenience' sake. Accordingly, the compound according to thepresent invention can have an intramolecular asymmetrical carbon, thusoccurring as optically active isomers or racemic modifications, and anyof such compounds are included in the present invention withoutlimitation. When there is crystal polymorphism, the compound accordingto the present invention may be in a single crystal form or a mixedcrystal form without limitation. Compound (I) or salts thereof may beanhydrides or hydrates, any of which fall under the claims in thespecification. Further, metabolites formed by decomposition of Compound(I) in vivo, and prodrugs of Compound (I) or salts thereof, also fallunder the claims in the specification.

[0022] The “halogen atom” used in the specification refers to an atomsuch as a fluorine atom, a chlorine atom, a bromine atom or an iodineatom, preferably a fluorine atom, a chlorine atom or a bromine atom.

[0023] The “C₁₋₆ alkyl group” represented by R¹, R², R³ and R⁴ in thespecification refers to an alkyl group having 1 to 6 carbon atoms, andexamples thereof include a methyl group, ethyl group, n-propyl group,iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group,tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group,1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group,2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group,1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group,1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutylgroup, 2-methylpentyl group, 3-methylpentyl group etc., preferably amethyl group, ethyl group, n-propyl group, iso-propyl group, n-butylgroup, iso-butyl group and tert-butyl group.

[0024] The “C₁₋₆ alkoxy group” represented by R¹, R², R³ and R⁴ in thespecification refers to an alkoxy group having 1 to 6 carbon atoms, andexamples thereof include a methoxy group, ethoxy group, n-propoxy group,iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy group,sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxygroup, sec-pentyloxy group, n-hexoxy group, iso-hexoxy group,1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group,2,2-dimethylpropyloxy group, 2-ethylpropoxy group,1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group,1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group,1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxygroup, 2,3-dimethylbutyloxy group, 1,3-dimethylbutyloxy group,2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group,3-methylpentoxy group, hexyloxy group etc., preferably a methoxy group,ethoxy group, n-propoxy group and iso-propoxy group.

[0025] The “C₁₋₆ alkoxycarbonyl group” represented by R¹, R², R³ and R⁴in the specification. refers to a group in which a C₁₋₆ alkoxy grouphaving the same meaning as defined above bound to a carbonyl group. Forexample, a methoxycarbonyl group, ethoxycarbonyl group,n-propoxycarbonyl group, iso-propoxycarbonyl group, n-butoxycarbonylgroup, iso-butoxycarbonyl group, tert-butoxycarbonyl group,pentyloxycarbonyl group, hexyloxycarbonyl group etc., preferably amethoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group andiso-propoxycarbonyl group.

[0026] The “C₁₋₆alkyl aminocarbonyloxy group” represented by R¹, R², R³and R⁴ in the specification refers to an aminocarbonyloxy group whosenitrogen atom has been substituted with a C₁₋₆alkyl group having thesame meaning as defined above, and examples thereof include amethylaminocarbonyloxy group, ethylaminocarbonyloxy group,n-propylaminocarbonyloxy group, iso-propylaminocarbonyloxy group,n-butylaminocarbonyloxy group, iso-butylaminocarbonyloxy group,tert-butylaminocarbonyloxy group, n-pentylaminocarbonyloxy group,iso-pentylaminocarbonyloxy group, neopentylaminocarbonyloxy group,hexylaminocarbonyloxy group, 1-methylpropylaminocarbonyloxy group,1-methyl butyl aminocarbonyloxy group, 2-methylbutylaminocarbonyloxygroup etc.

[0027] The “di (C₁₋₆ alkyl)-aminocarbonyloxy group” represented by R¹,R², R³ and R⁴ in the specification refers to an aminocarbonyloxy groupwhose nitrogen atom has been substituted with two C₁₋₆ alkyl groups, andexamples thereof include a dimethylaminocarbonyloxy group,diethylaminocarbonyloxy group, di(n-propyl)-aminocarbonyloxy group,di-(iso-propyl)-aminocarbonyloxy group, di(n-butyl)-aminocarbonyloxygroup, di(iso-butyl)-aminocarbonyloxy group,di-(tert-butyl)-aminocarbonyloxy group, di(n-pentyl)-aminocarbonyloxygroup, di-(iso-pentyl)-aminocarbonyloxy group,di-(neopentyl)-aminocarbonyloxy group, di-(n-hexyl)-aminocarbonyloxygroup, di-(1-methylpropyl)-aminocarbonyloxy group,di-(1-methylbutyl)-aminocarbonyloxy group,di-(2-methylbutyl)-aminocarbonyloxy group etc.

[0028] As the preferable mode of R¹, R², R³ and R⁴ in the specification,R¹, R^(2,) R³ and R⁴ are the same as or different from each other andeach represents a hydrogen atom, a halogen atom, a hydroxyl group, anitrile group, a C₁₋₆alkyl group or a C₁₋₆ alkoxy group; morepreferably, they are the same as or different from each other and eachrepresents a hydrogen atom, a halogen atom, a hydroxyl group, a nitrilegroup or a C₁₋₆alkoxy group; further preferably, they are the same as ordifferent from each other and each represents a hydrogen atom or aC₁₋₆alkoxy group; and the most preferably, R¹ and R⁴ represent ahydrogen atom while R² and R³ are the same as or different from eachother and each represents a C₁₋₆ alkoxy group (for example, a methoxygroup, ethoxy group etc.).

[0029] The “halogen atom” and “C₁₋₆ alkyl group” represented by R⁵ inthe specification refer to a halogen atom and C₁₋₆alkyl group eachhaving the same meaning as defined above.

[0030] The “C₂₋₆ alkenyl group” represented by R⁵ in the specificationrefers to an alkenyl group having 2 to 6 carbon atoms, and examplesthereof include linear or branched C₂₋₆ alkenyl groups such as a vinylgroup, allyl group, 1-propenyl group, isopropenyl group, 1-buten-1-ylgroup, 1-buten-2-yl group, 1-buten-3-yl group, 2-buten-1-yl group and2-buten-2-yl group, preferably a vinyl group, allyl group andisopropenyl group.

[0031] The “C₂₋₆ alkynyl group” represented by R⁵ in the specificationrefers to an alkynyl group having 2 to 6 carbon atoms, and examplesthereof include linear or branched C₂₋₆ alkynyl groups such as anethynyl group, 1-propynyl group, 2-propynyl group, butynyl group,pentynyl group and hexynyl group.

[0032] Preferable examples of R⁵ in the specification include a hydrogenatom and a halogen atom (for example, a fluorine atom, chlorine atom,bromine atom etc.).

[0033] The partial structure:

[0034] may be either a group represented by the formula >C(R⁶)—CH₂—(wherein R⁶ is a hydrogen atom or a halogen atom) or >C═CH—, preferablya group represented by the formula >C(R⁶)—CH₂— wherein R⁶ is a hydrogenatom or a halogen atom. Herein, the “halogen atom” represented by R⁶means an atom having the same meaning as the halogen atom in the abovedefinition, and R⁶ is preferably a hydrogen atom, fluorine atom,chlorine atom or bromine atom, more preferably a hydrogen atom orfluorine atom. That is, the group which can be represented by thepartial structure is more preferably the formula >CH—CH₂—, >C(F)—CH₂—,>C(Cl)—CH₂— or >C(Br)—CH₂—, further preferably the formula >CH—CH₂— or>C(F)—CH₂—.

[0035] The “halide ion” represented by X⁻ in the specification refers toa fluoride ion, chloride ion, bromide ion, iodide ion etc., preferably achloride ion, bromide ion and iodide ion, more preferably a chloride ionand bromide ion, most preferably a chloride ion. The “organic sulfonicacid ion” represented by X⁻ refers to a methanesulfonate ion,trifluoromethanesulfonate ion, ethanesulfonate ion, benzenesulfonateion, toluenesulfonate ion and camphor sulfonate ion etc.

[0036] In the specification, m is 0 or an integer from 1 to 5, whereuponthe partial structure:

[0037] represents (1) the formula >C(R⁶)—CH₂— or >C═CH— when m is 0, (2)the formula >C(R⁶)—(CH₂)₂— or >C=CH—(CH₂)— when m is 1, (3) the formula>C(R⁶)—(CH₂)₃— or >C═CH—(CH₂)₂— when m is 2, (4) the formula>C(R⁶)—(CH₂)₄— or >C═CH—(CH₂)₃— when m is 3, (5) the formula>C(R⁶)—(CH₂)₅— or >C═CH—(CH₂)₄— when m is 4, and (6) the formula>C(R⁶)—(CH₂)₆— or >C═CH—(CH₂)₅— when m is 5, respectively (in theformula, R⁶ has the same meaning as defined above). m is preferably 0, 2or 4, more preferably 0 or 2.

[0038] The best mode of the acetylcholinesterase inhibitor in thepresent invention includes, for example, those acetylcholinesteraseinhibitors comprising the following compounds. However, it goes withoutsaying that the embodiments of the present invention are not limited tothose acetylcholine esterase inhibitors comprising these compounds.

[0039] The acetylcholinesterase inhibitor comprises any one or two ormore 1-benzylpyridinium salts selected from:

[0040] 1-benzyl-4-(1-indanone-2-yl)methylpyridinium chloride;

[0041] 1-benzyl-4-[(4-methoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0042] 1-benzyl-4-[(5-methoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0043] 1-benzyl-4-[(6-methoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0044] 1-benzyl-4-[(7-methoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0045] 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0046] 1-benzyl-4-[(5,7-dimethoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0047] 1-benzyl-4-[(4,7-dimethoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0048] 1-benzyl-4-[(4,5-dimethoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0049] 1-benzyl-4-[(6,7-dimethoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0050] 1-benzyl-4-[(5,6,7-trimethoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0051] 1-benzyl-4-[(5,6-diethoxy-1-indanone)-2-yl]methylpyridiniumchloride;

[0052] 1-benzyl-4-(1-indanone-2-yl)methylpyridinium bromide;

[0053] 1-benzyl-4-[(4-methoxy-1-indanone)-2-yl]methylpyridinium bromide;

[0054] 1-benzyl-4-[(5-methoxy-1-indanone)-2-yl]methylpyridinium bromide;

[0055] 1-benzyl-4-[(6-methoxy-1-indanone)-2-yl]methylpyridinium bromide;

[0056] 1-benzyl-4-[(7-methoxy-1-indanone)-2-yl]methylpyridinium bromide;

[0057] 1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpyridiniumbromide;

[0058] 1-benzyl-4-[(5,7-dimethoxy-1-indanone)-2-yl]methylpyridiniumbromide;

[0059] 1-benzyl-4-[(4,7-dimethoxy-1-indanone)-2-yl]methylpyridiniumbromide;

[0060] 1-benzyl-4-[(4,5-dimethoxy-1-indanone)-2-yl]methylpyridiniumbromide;

[0061] 1-benzyl-4-[(6,7-dimethoxy-1-indanone)-2-yl]methylpyridiniumbromide;

[0062] 1-benzyl-4-[(5,6,7-trimethoxy-1-indanone)-2-yl]methylpyridiniumbromide; and

[0063] 1-benzyl-4-[(5,6-diethoxy-1-indanone)-2-yl]methylpyridiniumbromide.

[0064] The 1-benzylpyridinium salt represented by the above formula (I)as the active ingredient in the acetylcholinesterase inhibitor accordingto the present invention can be produced by a known method or itsanalogous method. Typical methods include a production method described,for example, in JP-A 11-263774 and a process for producing abenzylpyridinium salt (I) described in JP-A 8-225527.

[0065] The starting compound in production of the 1-benzylpyridiniumsalt (I) as the active ingredient in the acetylcholinesterase inhibitoraccording to the present invention may have formed a salt or a hydrateand is not particularly limited insofar as the reaction is notinhibited. Further, when Compound (I) according to the present inventionis obtained in a free form, it can be converted in a usual manner into asalt which Compound (I) may form. Further, the resulting various isomers(for example, geometric isomer, optical isomer based on asymmetriccarbon, stereoisomer, tautomer etc.) of Compound (I) according to thepresent invention can be purified and isolated by usual separatingmeans, for example, re-crystallization, diastereomer salt method, enzymefractionation method, and various kinds of chromatography (for example,thin layer chromatography, column chromatography, gas chromatographyetc.).

[0066] The acetylcholinesterase preparation according to the presentinvention can be manufactured by a conventional method, and preferablepreparation forms include tablets, powders, fine granules, granules,coated tablets, capsules, syrups, troches, inhalations, suppositories,injections, ointments, eye ointments, eye drops, nose drops, ear drops,poultices and lotions. Ordinarily used fillers, binders, disintegratingagents, lubricants, coloring agents, flavoring agents and as necessarystabilizers, emulsifiers, absorption promoters, surfactants, pHadjusters, preservatives and antioxidants can be used in pharmaceuticalmanufacturing, and ingredients used generally as starting materials forpharmaceutical preparations can be blended in a usual manner formanufacturing. These ingredients include e.g. (1) animal and vegetableoils such as soybean oil, tallow and synthetic glyceride; (2)hydrocarbons such as liquid paraffin, squalane and solid paraffin; (3)ester oils such as octyldodecyl myristate and isopropyl myristate; (4)higher alcohols such as cetostearyl alcohol and behenyl alcohol; (5)silicon resin; (6) siliconoil; (7) surfactants such as polyoxyethylenefatty ester, sorbitan fatty ester, glycerin fatty ester, polyoxyethylenesorbitan fatty ester, polyoxyethylene hardened castor oil andpolyoxyethylene polyoxypropylene block copolymer; (8) water-solublepolymers such as hydroethyl cellulose, polyacrylic acid, carboxyvinylpolymer, polyethylene glycol, polyvinyl pyrrolidone and methylcellulose; (9) lower alcohols such as ethanol and isopropanol; (10)polyvalent alcohols such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; (11) sugars such as glucose and sucrose; (12)inorganic powder such as silicic anhydride, aluminum magnesium silicateand aluminum silicate; and (13) pure water.

[0067] 1) The fillers include e.g. lactose, corn starch, sucrose,glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxideetc.; 2) the binders include e.g. polyvinyl alcohol, polyvinyl ether,methyl cellulose, ethyl cellulose, arabic gum, tragacanth, gelatin,shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene blockpolymer, meglumine, calcium citrate, dextrin, pectin etc.; 3) thedisintegrating agents include e.g. starch, agar, gelatin powder,crystalline cellulose, calcium carbonate, sodium bicarbonate, calciumcitrate, dextrin, pectin, carboxymethyl cellulose calcium etc.; 4) thelubricants include e.g. magnesium stearate, talc, polyethylene glycol,silica, hardened vegetable oil etc.; 5) the coloring agents include e.g.those which are approved to be added to pharmaceutical preparations; 6)the flavoring agents include cocoa powder, menthol, aromatic powder,peppermint oil, borneol, cinnamon powder etc.; and 7) the antioxidantsinclude those which are approved to be added to pharmaceuticalpreparations such as ascorbic acid and α-tocopherol.

[0068] 1) The oral preparation is produced by mixing Compound (I) or asalt thereof with fillers and if necessary with a binder, adisintegrating agent, a lubricant, a coloring agent, flavoring agentsetc.; and then forming it in a usual manner into powders, fine granules,granules, tablets, coated tablets, capsules etc. 2) The tablets andgranules may be coated with a sugar or gelatin coating or if necessarywith another suitable coating. 3) The liquid preparations such assyrups, injections, eye drops etc. are prepared by mixing with a pHadjuster, a solubilizer and an isotonizing agent together with, ifnecessary, a solubilizing aid, a stabilizer, a buffer, a suspensionagent and an antioxidant, followed by forming it into the preparationsin a usual manner. The liquid preparation may be formed into afreeze-dried product and the injection can be administeredintravenously, subcutaneously or intramuscularly. Preferable examples ofthe suspension agent include methyl cellulose, Polysorbate 80,hydroxyethyl cellulose, arabic gum, tragacanth powder, sodiumcarboxymethyl cellulose, polyoxyethylene sorbitan monolaurate etc.;preferable examples of the solubilizing aid include polyoxyethylenehardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylenesorbitan monolaurate etc.; preferable examples of the stabilizer includesodium sulfite, sodium metasulfite, ether etc.: preferable examples ofthe preservative include methyl p-oxybenzoate, ethyl p-oxybenzoate,sorbic acid, phenol, cresol, chlorocresol etc. 4) The agent for externalapplication can be produced in any of the conventional processes withoutany limit to the process thereof. The starting base material can makeuse of various starting materials ordinarily used in pharmaceuticalpreparations, non-pharmaceutical preparations, cosmetics etc.; forexample, the starting base material includes animal and vegetable oils,mineral oil, ester oil, waxes, higher alcohols, fatty acids, siliconoil,surfactants, phospholipids, alcohols, polyvalent alcohols, water-solublepolymers, clay minerals, pure water etc., and if necessary, a pHadjuster, an antioxidant, a chelating agent, a preservative, a coloringagent, a perfume etc. can further be added. Further, ingredients havinga differentiation-inducing action, a blood-stream promoting agent, asterilizer, an antiinflammatory agent, a cell activator, vitamins, aminoacids, a humectant and a keratin solubilizer can also be incorporated asnecessary.

[0069] Although the dose of the acetylcholinesterase preparationaccording to the present invention is varied depending on severity ofsymptoms, age, sex, body weight, administration form, type of salt,chemical sensitivity and type of disease, and in the case of an adult,it is administered in a dose of generally about 30 μg to 1000 μg,preferably 100 μg to 500 μg and more preferably 100 μg to 100 μg fororal administration, or about 1 to3000 μg/kg, preferably 3 to 10000μg/kg for injection per day in one or several portions.

[0070] The acetylcholinesterase inhibitor according to the presentinvention exhibits an excellent inhibitory effect onacetylcholinesterase, and is useful as an agent for treating, preventingor improving senile dementia, cerebrovascular dementia or attentiondeficit hyperactivity disorder. In particular, it is useful as an agentfor treating, preventing or improving Alzheimer type senile dementia.

EXAMPLES

[0071] Among the specific examples of the compounds as the activeingredient in the acetylcholinesterase inhibitor according to thepresent invention, the best mode is described below. The followingexamples and test example are described merely for illustrativepurposes, and the compounds according to the present invention is notlimited by the following specific examples in any case. The presentinvention can be carried out to the maximum by those skilled in the artby various modifications not only to the following examples but also toclaims in the specification, and such modifications fall under patentclaims of the specification.

Example 1 1-Benzyl-4-[(5.6-dimethoxy-1-indanone)-2-yl]methylpyridiniumbromide

[0072]

[0073] 30 ml acetonitrile was added to 1.00 g (3.53 mmol) of5,6-dimethoxy-2-(4-pyridyl)methyl-1-indanone, and the mixture wasdissolved by heating under ref lux. Then, 0.50 ml (4.21 mmol) benzylbromide was added thereto. After heating under reflux for further 2.5hours, it was left for cooling to room temperature and evaporated. 50 mln-hexane was added to the residue. The precipitated crystals wereseparated by filtration and dried, to give 1.60 g of the title compoundas pale yellow crystals (yield: quantitative). Melting point: 173-177°C. ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm) 2.70(1H, dd, J=3.6 Hz, J=16.4Hz),3.01 (1H, dd, J=9.2 Hz, J=14 Hz), 3.12 (1H, dd, J=7.6 Hz, J=16.4 Hz),3.16-3.24 (1H, m), 3.30-3.98 (1H, m), 3.77 (3H,s), 3.83 (3H, s), 5.81(2H, s), 7.06 (1H, s), 7.07 (1H, s), 7.38-7.48(3H, m), 7.50-7.56 (2H,m), 8.13 (2H, d, J=6.4 Hz), 9.14 (2H, d, J=6.4 Hz). ESI−MS: m/z=374(M−Br)+.

Example 2 1-Benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpyridiniumchloride

[0074]

Example 3 1-Benzyl-4-[(1-indanone)-2-yl]methylpyridinium bromide

[0075]

Example 4 1-Benzyl-4-[(5-methoxy-1-indanone)-2-yl]methylpyridiniumbromide

[0076]

Example 51-Benzyl-4-[2-[(5,6-dimethoxy-1-indanone)-2-yl]ethyl]pyridinium bromide

[0077]

Example 61-Benzyl-4-[3-[(5,6-dimethoxy-1-indanone)-2-yl]propyl]pyridinium bromide

[0078]

Example 71-Benzyl-4-[(5,6-dimethoxy-1-indanone)-2-ylidene]methylpyridiniumbromide

[0079]

Example 81-(3-Fluorobenzyl)-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpyridiniumbromide

[0080]

Example 91-(3-Methylbenzyl)-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpyridiniumbromide

[0081]

Example 101-(4-Hydroxybenzyl)-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpyridiniumbromide

[0082]

Example 111-Benzyl-4-[(5,6-dimethoxy-2-fluoro-1-indanone)-2-yl]methylpyridiniumbromide

[0083]

Example 121-(4-Hydroxybenzyl)-4-[(5,6-dimethoxy-2-fluoro-1-indanone)-2-yl]methylpyridiniumbromide

[0084]

Test Example

[0085] Hereinafter, a pharmacological test example is shown toillustrate the usefulness of the compound according to the presentinvention as a medicament.

Inhibitory Effect on Acetylcholinesterase In Vitro

[0086] 1) Test Method

[0087] Using a rat brain homogenate as a source of acetylcholinesterase,the esterase activity was determined in accordance with the method ofEllman et al¹⁾. Acetylthiocholine (as a substrate), a test compound andDTNB (5,5′-dithiobis(2-nitrobenzoic acid)) were added to the rat brainhomogenate, and incubated. Then, the resulting yellow product producedby the reaction of the resulting thiocholine with DTNB was determinedfor the change in absorbance at 412 nm, to determine theacethylcholinesterase activity.

[0088] The inhibitory effect of each test compound onacethylcholinesterase was determined in terms of 50% inhibitoryconcentration (IC₅₀)

[0089] Each of the compounds was used after dissolved in physiologicalsaline.

[0090]¹⁾; Ellman. G. L., Courtney, K. D., Andres, V. and Featherstone,R. M., (1961), Biochem. Pharmacol., 7, 88-95.

[0091] The pharmaceutical compositions comprising the title compounds ofthe above-mentioned Examples 1 to 12 exhibited an excellentacetylcholinesterase inhibitory effect. For example, the test resultwhere the title compound of Example 1 was used is as follows: TABLE 1Test Compound IC₅₀ (nM) Example 1 3.8 Donepezil hydrochloride 6.7

1. An acetylcholinesterase inhibitor comprising a 1-benzylpyridiniumsalt represented by the formula:

wherein R¹, R², R³ and R⁴ are the same as or different from each otherand each represents a hydrogen atom, a halogen atom, a hydroxyl group, anitrile group, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₁₋₆alkoxycarbonyl group, a C₁₋₆ alkylaminocarbonyloxy group or a di (C₁₋₆alkyl)-aminocarbonyloxy group; R⁵ represents a hydrogen atom, a halogenatom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group or a C₂₋₆ alkynyl group;the partial structure:

 means a group represented by the formula >C(R⁶)—CH₂— (wherein R⁶ is ahydrogen atom or a halogen atom) or >C═CH—; X⁻ represents a halide ionor organic sulfonic acid ion; m is 0 or an integer from 1 to
 5. 2. Theacetylcholinesterase inhibitor according to claim 1, wherein R¹, R², R³and R⁴ are the same as or different from each other and each representsa hydrogen atom or a C₁₋₆ alkoxy group.
 3. The acetylcholinesteraseinhibitor according to claim 1, wherein R¹, R², R³ and R⁴ are the sameas or different from each other and each represents a hydrogen atom or amethoxy group.
 4. The acetylcholinesterase inhibitor according to claim1, wherein R¹ and R⁴ represent a hydrogen atom; and R² and R³ representa methoxy group.
 5. The acetylcholinesterase inhibitor according toclaim 1, wherein R⁵ is a hydrogen atom.
 6. The acetylcholinesteraseinhibitor according to claim 1, wherein the partial structure:

is a group represented by the formula >C(R⁶)—CH₂— (wherein R⁶ representsa hydrogen atom or a halogen atom).
 7. The acetylcholinesteraseinhibitor according to claim 1, wherein m is 0, 2 or
 4. 8. Theacetylcholinesterase inhibitor according to claim 1, wherein the halideion represented by X⁻ is a chloride ion, bromide ion or iodide ion. 9.The acetylcholinesterase inhibitor according to claim 1, wherein theorganic sulfonic acid ion represented by X⁻ is methanesulfonate ion,trifluoromethanesulfonate ion, ethanesulfonate ion, benzenesulfonateion, toluenesulfonate ion and camphorsulfonate ion.
 10. Theacetylcholinesterase inhibitor according to claim 1, wherein the1-benzylpyridinium salt is a compound represented by the formula:

wherein R¹, R², R³, R⁴ and X⁻ have the same meanings as defined above;and n is an integer from 1 to
 6. 11. The acetylcholinesterase inhibitoraccording to claim 1, wherein the 1-benzylpyridinium salt is a compoundrepresented by the formula:

wherein R¹, R², R³, R⁴ and X⁻ have the same meanings as defined above;and p is an integer from 0 to
 5. 12. The acetylcholinesterase inhibitoraccording to claim 1, which is an agent for treating, preventing orimproving senile dementia, cerebrovascular dementia or attention deficithyperactivity disorder.
 13. The acetylcholinesterase inhibitor accordingto claim 12, wherein the senile dementia is Alzheimer type seniledementia.
 14. A pharmaceutical preparation comprising a1-benzylpyridinium salt represented by the formula:

wherein R¹, R², R³, R⁴, R⁵, the partial structure:

 X⁻ and m have the same meanings as defined above.
 15. Use of a1-benzylpyridinium salt represented by the formula:

(wherein R¹, R², R³, R⁴, R⁵, the partial structure:

 X⁻ and m have the same meanings as defined above) for producing anacetylcholinesterase inhibitor.
 16. A method of preventing, treating orimproving a disease against which an inhibitory action onacetylcholinesterase is efficacious for prevention, treatment orimprovement, by administering a pharmacologically effective dose of the1-benzylpyridinium salt represented by the formula (I) according toclaim 1 to a patient.
 17. The use according to claim 15, wherein in theformula (I), R¹, R², R³, R⁴, R⁵, the partial structure:

and m have the same meanings as defined above; and X⁻ is a chloride ionor bromide ion.
 18. The method according to claim 16, wherein in theformula (I), R¹, R², R³, R⁴, R⁵, the partial structure:

and m have the same meanings as defined above; and X⁻ is a chloride ionor bromide ion.